Many members of the HDAC family require zinc (Zn) to function properly. For instance, the isozymes histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) are zinc-dependent histone deacetylases that possesses histone deacetylase activity. Other family members include HDACs 1-5 and 7-10. (De Ruijter et al, Biochem. J. 2003. 370; 737-749).
HDAC6 is a class II HDAC known to deacetylate and associate with α-tubulin, cortactin, heat shock protein 90, α-catenin, glucose-regulated protein 78 kDa, myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homolog subfamily A member 1 (reviewed in Li et al, FEBS J. 2013, 280: 775-93; Zhang et al, Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6 inhibition could have a potential benefit include cancer (reviewed in Aldana-Masangkay et al, J Biomed. Biotechnol. 2011, 875824), specifically: multiple myeloma (Hideshima et al, Proc. Natl. Acad. Sci. USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al, Biochem. Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro et al, Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al, Cancer Res. 2008, 68(18):7561-7569; Park et al, Oncol. Rep. 2011, 25: 1677-81; Rey et al, Eur. J Cell Biol. 2011, 90: 128-35); prostate cancer (Seidel et al, Biochem. Pharmacol. 2015 (15)00714-5); pancreatic cancer (Nawrocki et al, Cancer Res. 2006, 66(7):3773-3781); renal cancer (Cha et al, Clin. Cancer Res. 2009, 15(3): 840-850); hepatocellular cancer (Ding et al, FEBS Lett. 2013, 587:880-6; Kanno et al, Oncol. Rep. 2012, 28: 867-73); lymphomas (Ding et al, Cancer Cell Int. 2014, 14:139; Amengual et al, Clin Cancer Res. 2015, 21(20):4663-75); and leukemias such as acute myeloid leukemia (AML) (Fiskus et al, Blood 2008, 112(7):2896-2905) and acute lymphoblastic leukemia (ALL) (Rodriguez-Gonzalez et al, Blood 2008, 1 12(1 1): Abstract 1923)).
HDAC11 is a class IV HDAC (Gao et al, J Biol Chem. 2002, Jul. 12; 277(28):25748-55) reported to deacetylate or associate with cell cycle-related proteins including Cdt1 (Glozak et al, J Biol Chem. 2009, Apr. 24; 284(17):11446-53), geminin (Wong et al, Cell Cycle. 2010, Nov. 1; 9(21):4351-63), BubR1 (Watanabe et al, Cell Rep. 2014, Apr. 24; 7(2):552-64), and Cdc25(Lozada et al, Oncotarget. 2016, Mar. 7). HDAC11 was also reported to function in RNA splicing as part of the survival of motor neuron complex (Joshi et al, Mol Syst Biol. 2013, 9:672). Diseases in which HDAC11 inhibition could have potential benefit include cancer (Deubzer et al, Int J Cancer. 2013, May 1; 132(9):2200-8) and specifically, Hodgkin lymphoma (Buglio et al, Blood. 2011, Mar. 10; 117(10):2910-7).
Inhibition of HDAC6 may also have a role in cardiovascular disease, including pressure overload, chronic ischemia, and infarction-reperfusion injury (Tannous et al, Circulation 2008, 117(24):3070-3078); bacterial infection, including those caused by uropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008, 284(1):446-454); neurological diseases caused by accumulation of intracellular protein aggregates such as Alzheimer's, Parkinson's and Huntington's disease (reviewed in Simoes-Pires et al, Mol. Neurodegener. 2013, 8: 7) or central nervous system trauma caused by tissue injury, oxidative-stress induced neuronal or axonal degeneration (Rivieccio et al, Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); and inflammation and autoimmune diseases through enhanced T cell-mediated immune tolerance at least in part through effects on regulatory T cells, including rheumatoid arthritis, psoriasis, spondylitis arthritis, psoriatic arthritis, multiple sclerosis, lupus, colitis and graft versus host disease (reviewed in Wang et al, Nat. Rev. Drug Disc. 2009 8(12):969-981; Vishwakarma et al, Int. Immunopharmacol. 2013, 16:72-8; Kalin et al, J. Med. Chem. 2012, 55:639-51); and fibrotic disease, including kidney fibrosis (Choi et al, Vascul. Pharmacol. 2015 72:130-140). Inhibition of HDAC11 may also have a role in inflammatory or autoimmune diseases through effects on IL-10 on immune cells including antigen presenting cells and myeloid-derived suppressor cells (Villagra et al, Nat Immunol. 2009, January; 10(1):92-100; Cheng et al, Mol Immunol. 2014, July; 60(1):44-53; Sahakian et al, Mol Immunol. 2015, February; 63(2):579-85).
Four HDAC inhibitors are currently approved for the treatment of some cancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) for the treatment of cutaneous T cell lymphoma and multiple myeloma; Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral T cell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment of multiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatment of peripheral T cell lymphoma. However, these drugs are of limited effectiveness and can give rise to unwanted side effects. Thus, there is a need for HDAC inhibitors with an improved safety-efficacy profile.